tbuckley/cabot-search huggingface dataset:
Navigating the Evolving Treatment Landscape of Diffuse Large B-Cell Lymphoma
Authors: Loretta J. Nastoupil, Nancy L. Bartlett
Journal: Journal of Clinical Oncology (2022)

Diffuse large B-cell lymphoma, the most common subtype of non-Hodgkin lymphoma, comprises a heterogenous group of morphologically, genetically, and clinically distinct diseases. Several recent advances have affected the treatment landscape, which had been mostly stagnant for the past few decades. We will review the practice-changing studies in frontline (POLARIX), early relapse (ZUMA-7 and TRANSFORM), and multiple recurrent (ZUMA-1, JULIET, TRANSCEND, L-MIND, and LOTIS-2) stages and discuss how the treatment landscape may evolve with the emergence of bispecific antibodies.
Optimization of the proliferation and persistency of CAR T cells derived from human induced pluripotent stem cells
Authors: Tatsuki Ueda, Sara Shiina, Shoichi Iriguchi, Seitaro Terakura, Yohei Kawai, Ryotaro Kabai, Satoko Sakamoto, Akira Watanabe, Kohei Ohara, Bo Wang, Huaigeng Xu, Atsutaka Minagawa, Akitsu Hotta, Knut Woltjen, Yasushi Uemura, Yuzo Kodama, Hiroshi Seno, Tetsuya Nakatsura, Koji Tamada, Shin Kaneko
Journal: Nature Biomedical Engineering (2022)

Abstract The effectiveness of chimaeric antigen receptor (CAR) T-cell immunotherapies against solid tumours relies on the accumulation, proliferation and persistency of T cells at the tumour site. Here we show that the proliferation of CD8αβ cytotoxic CAR T cells in solid tumours can be enhanced by deriving and expanding them from a single human induced-pluripotent-stem-cell clone bearing a CAR selected for efficient differentiation. We also show that the proliferation and persistency of the effector cells in the tumours can be further enhanced by genetically knocking out diacylglycerol kinase, which inhibits antigen-receptor signalling, and by transducing the cells with genes encoding for membrane-bound interleukin-15 (IL-15) and its receptor subunit IL-15Rα. In multiple tumour-bearing animal models, the engineered hiPSC-derived CAR T cells led to therapeutic outcomes similar to those of primary CD8 T cells bearing the same CAR. The optimization of effector CAR T cells derived from pluripotent stem cells may aid the development of long-lasting antigen-specific T-cell immunotherapies for the treatment of solid tumours.
Effect of Calorie-Unrestricted Low-Carbohydrate, High-Fat Diet Versus High-Carbohydrate, Low-Fat Diet on Type 2 Diabetes and Nonalcoholic Fatty Liver Disease
Authors: Camilla Dalby Hansen, Eva-Marie Gram-Kampmann, Johanne Kragh Hansen, Mie Balle Hugger, Bjørn Stæhr Madsen, Jane Møller Jensen, Sara Olesen, Nikolaj Torp, Ditlev Nytoft Rasmussen, Maria Kjærgaard, Stine Johansen, Katrine Prier Lindvig, Peter Andersen, Katrine Holtz Thorhauge, Jan Christian Brønd, Pernille Hermann, Henning Beck-Nielsen, Sönke Detlefsen, Torben Hansen, Kurt Højlund, Maja Sofie Thiele, Mads Israelsen, Aleksander Krag
Journal: Annals of Internal Medicine (2022)

It remains unclear if a low-carbohydrate, high-fat (LCHF) diet is a possible treatment strategy for type 2 diabetes mellitus (T2DM), and the effect on nonalcoholic fatty liver disease (NAFLD) has not been investigated.To investigate the effect of a calorie-unrestricted LCHF diet, with no intention of weight loss, on T2DM and NAFLD compared with a high-carbohydrate, low-fat (HCLF) diet.6-month randomized controlled trial with a 3-month follow-up. (ClinicalTrials.gov: NCT03068078).Odense University Hospital in Denmark from November 2016 until June 2020.165 participants with T2DM.Two calorie-unrestricted diets: LCHF diet with 50 to 60 energy percent (E%) fat, less than 20E% carbohydrates, and 25E% to 30E% proteins and HCLF diet with 50E% to 60E% carbohydrates, 20E% to 30E% fats, and 20E% to 25E% proteins.Glycemic control, serum lipid levels, metabolic markers, and liver biopsies to assess NAFLD.The mean age was 56 years (SD, 10), and 58% were women. Compared with the HCLF diet, participants on the LCHF diet had greater improvements in hemoglobin A1c (mean difference in change, -6.1 mmol/mol [95% CI, -9.2 to -3.0 mmol/mol] or -0.59% [CI, -0.87% to -0.30%]) and lost more weight (mean difference in change, -3.8 kg [CI, -6.2 to -1.4 kg]). Both groups had higher high-density lipoprotein cholesterol and lower triglycerides at 6 months. Changes in low-density lipoprotein cholesterol were less favorable in the LCHF diet group than in the HCLF diet group (mean difference in change, 0.37 mmol/L [CI, 0.17 to 0.58 mmol/L] or 14.3 mg/dL [CI, 6.6 to 22.4 mg/dL]). No statistically significant between-group changes were detected in the assessment of NAFLD. Changes were not sustained at the 9-month follow-up.Open-label trial, self-reported adherence, unintended weight loss, and lack of adjustment for multiple comparisons.Persons with T2DM on a 6-month, calorie-unrestricted, LCHF diet had greater clinically meaningful improvements in glycemic control and weight compared with those on an HCLF diet, but the changes were not sustained 3 months after intervention.Novo Nordisk Foundation.
Long noncoding RNA LEENE promotes angiogenesis and ischemic recovery in diabetes models
Authors: Xiaofang Tang, Yingjun Luo, Dongqiang Yuan, Riccardo Calandrelli, Naseeb Kaur Malhi, Kiran Sriram, Yifei Miao, Chih-Hong Lou, Walter Tsark, Alonso Tapia, Aleysha T. Chen, Guangyu Zhang, Daniel Roeth, Markus Kalkum, Zhao V. Wang, Shu Chien, Rama Natarajan, John P. Cooke, Sheng Zhong, Zhen Bouman Chen
Journal: Journal of Clinical Investigation (2022)

Impaired angiogenesis in diabetes is a key process contributing to ischemic diseases such as peripheral arterial disease. Epigenetic mechanisms, including those mediated by long noncoding RNAs (lncRNAs), are crucial links connecting diabetes and the related chronic tissue ischemia. Here we identify the lncRNA that enhances endothelial nitric oxide synthase (eNOS) expression (LEENE) as a regulator of angiogenesis and ischemic response. LEENE expression was decreased in diabetic conditions in cultured endothelial cells (ECs), mouse hind limb muscles, and human arteries. Inhibition of LEENE in human microvascular ECs reduced their angiogenic capacity with a dysregulated angiogenic gene program. Diabetic mice deficient in Leene demonstrated impaired angiogenesis and perfusion following hind limb ischemia. Importantly, overexpression of human LEENE rescued the impaired ischemic response in Leene-knockout mice at tissue functional and single-cell transcriptomic levels. Mechanistically, LEENE RNA promoted transcription of proangiogenic genes in ECs, such as KDR (encoding VEGFR2) and NOS3 (encoding eNOS), potentially by interacting with LEO1, a key component of the RNA polymerase II-associated factor complex and MYC, a crucial transcription factor for angiogenesis. Taken together, our findings demonstrate an essential role for LEENE in the regulation of angiogenesis and tissue perfusion. Functional enhancement of LEENE to restore angiogenesis for tissue repair and regeneration may represent a potential strategy to tackle ischemic vascular diseases.
Bone Turnover Markers: Basic Biology to Clinical Applications
Authors: Marian Schini, Tatiane Vilaca, Fatma Gossiel, Syazrah Salam, Richard Eastell
Journal: Endocrine Reviews (2022)

Bone turnover markers (BTMs) are used widely, in both research and clinical practice. In the last 20 years, much experience has been gained in measurement and interpretation of these markers, which include commonly used bone formation markers (bone alkaline phosphatase, osteocalcin, and procollagen I N-propeptide); and commonly used resorption markers (serum C-telopeptides of type I collagen, urinary N-telopeptides of type I collagen, and tartrate-resistant acid phosphatase type 5b). BTMs are usually measured by enzyme-linked immunosorbent assay or automated immunoassay. Sources contributing to BTM variability include uncontrollable factors (eg, age, gender, ethnicity) and controllable factors, particularly relating to collection conditions (eg, fasting/feeding state, and timing relative to circadian rhythms, menstrual cycling, and exercise). Pregnancy, season, drugs, and recent fracture(s) can also affect BTMs. BTMs correlate with other methods of assessing bone turnover, such as bone biopsies and radiotracer kinetics, and can usefully contribute to diagnosis and management of several diseases such as osteoporosis, osteomalacia, Paget's disease, fibrous dysplasia, hypophosphatasia, primary hyperparathyroidism, and chronic kidney disease-mineral bone disorder.
Clonal Hematopoiesis and Risk of Incident Lung Cancer
Authors: Ruiyi Tian, Brian Wiley, Jie Liu, Xiaoyu Zong, Buu Truong, Stephanie Zhao, Md Mesbah Uddin, Abhishek Niroula, Christopher A. Miller, Semanti Mukherjee, Brendan T. Heiden, Jingqin Luo, Varun Puri, Benjamin D. Kozower, Matthew J. Walter, Li Ding, Daniel C. Link, Christopher I. Amos, Benjamin L. Ebert, Ramaswamy Govindan, Pradeep Natarajan, Kelly L. Bolton, Yin Cao
Journal: Journal of Clinical Oncology (2022)

To prospectively examine the association between clonal hematopoiesis (CH) and subsequent risk of lung cancer.
Early adversity promotes binge-like eating habits by remodeling a leptin-responsive lateral hypothalamus–brainstem pathway
Authors: Sora Shin, In-Jee You, Minju Jeong, Yeeun Bae, Xiao-Yun Wang, Mikel Leann Cawley, Abraham Han, Byung Kook Lim
Journal: Nature Neuroscience (2022)

Abstract Early-life trauma (ELT) is a risk factor for binge eating and obesity later in life, yet the neural circuits that underlie this association have not been addressed. Here, we show in mice that downregulation of the leptin receptor (Lepr) in the lateral hypothalamus (LH) and its effect on neural activity is crucial in causing ELT-induced binge-like eating and obesity upon high-fat diet exposure. We also found that the increased activity of Lepr-expressing LH (LH Lepr ) neurons encodes sustained binge-like eating in ELT mice. Inhibition of LH Lepr neurons projecting to the ventrolateral periaqueductal gray normalizes these behavioral features of ELT mice. Furthermore, activation of proenkephalin-expressing ventrolateral periaqueductal gray neurons, which receive inhibitory inputs from LH Lepr neurons, rescues ELT-induced maladaptive eating habits. Our results identify a circuit pathway that mediates ELT-induced maladaptive eating and may lead to the identification of novel therapeutic targets for binge eating and obesity.
A Genetically Encoded Magnetic Resonance Imaging Reporter Enables Sensitive Detection and Tracking of Spontaneous Metastases in Deep Tissues
Authors: Nivin N. Nyström, Sean W. McRae, Francisco M. Martinez, John J. Kelly, Timothy J. Scholl, John A. Ronald
Journal: Cancer Research (2022)

Abstract Metastasis is the leading cause of cancer-related death. However, it remains a poorly understood aspect of cancer biology, and most preclinical cancer studies do not examine metastasis, focusing solely on the primary tumor. One major factor contributing to this paradox is a gap in available tools for accurate spatiotemporal measurements of metastatic spread in vivo. Here, our objective was to develop an imaging reporter system that offers sensitive three-dimensional (3D) detection of cancer cells at high resolutions in live mice. An organic anion-transporting polypeptide 1b3 (oatp1b3) was used as an MRI reporter gene, and its sensitivity was systematically optimized for in vivo tracking of viable cancer cells in a spontaneous metastasis model. Metastases with oatp1b3-MRI could be observed at the single lymph node level and tracked over time as cancer cells spread to multiple lymph nodes and different organ systems in individual animals. While initial single lesions were successfully imaged in parallel via bioluminescence, later metastases were largely obscured by light scatter from the initial node. Importantly, MRI could detect micrometastases in lung tissue comprised on the order of 1,000 cancer cells. In summary, oatp1b3-MRI enables longitudinal tracking of cancer cells with combined high resolution and high sensitivity that provides 3D spatial information and the surrounding anatomical context. Significance: An MRI reporter gene system optimized for tracking metastasis in deep tissues at high resolutions and able to detect spontaneous micrometastases in lungs of mice provides a useful tool for metastasis research.
Omicron sublineage recombinant XBB evades neutralising antibodies in recipients of BNT162b2 or CoronaVac vaccines
Authors: Xiaojuan Zhang, Lin-Lei Chen, Jonathan Daniel Ip, Wan-Mui Chan, Ivan Fan-Ngai Hung, Kwok-Yung Yuen, Xin Li, Kelvin Kai-Wang To
Journal: The Lancet Microbe (2022)
Impaired SARS-CoV-2 Variant Neutralization and CD8+ T-cell Responses Following 3 Doses of mRNA Vaccines in Myeloma: Correlation with Breakthrough Infections
Authors: Maryam I. Azeem, Ajay K. Nooka, Uma Shanmugasundaram, Narayanaiah Cheedarla, Sayalee Potdar, Renee Julia Manalo, Alberto Moreno, Jeffrey M. Switchenko, Suneethamma Cheedarla, Deon Bryant Doxie, Roman Radzievski, Madison Leigh Ellis, Kelly E. Manning, Bushra Wali, Rajesh M. Valanparambil, Kathryn T. Maples, Essence Baymon, Jonathan L. Kaufman, Craig C. Hofmeister, Nisha S. Joseph, Sagar Lonial, John D. Roback, Alessandro Sette, Rafi Ahmed, Mehul S. Suthar, Andrew S. Neish, Madhav V. Dhodapkar, Kavita M. Dhodapkar
Journal: Blood Cancer Discovery (2022)

Patients with multiple myeloma (MM) mount suboptimal neutralizing antibodies (nAb) following 2 doses of SARS-CoV-2 mRNA vaccines. Currently, circulating SARS-CoV-2 variants of concern (VOC) carry the risk of breakthrough infections. We evaluated immune recognition of current VOC including BA.1, BA.2, and BA.5 in 331 racially representative patients with MM following 2 or 3 doses of mRNA vaccines. The third dose increased nAbs against WA1 in 82%, but against BA variants in only 33% to 44% of patients. Vaccine-induced nAbs correlated with receptor-binding domain (RBD)-specific class-switched memory B cells. Vaccine-induced spike-specific T cells were detected in patients without seroconversion and cross-recognized variant-specific peptides but were predominantly CD4+ T cells. Detailed clinical/immunophenotypic analysis identified features correlating with nAb/B/T-cell responses. Patients who developed breakthrough infections following 3 vaccine doses had lower live-virus nAbs, including against VOC. Patients with MM remain susceptible to SARS-CoV-2 variants following 3 vaccine doses and should be prioritized for emerging approaches to elicit variant-nAb and CD8+ T cells.Three doses of SARS-CoV-2 mRNA vaccines fail to yield detectable VOC nAbs in nearly 60% and spike-specific CD8+ T cells in >80% of myeloma patients. Patients who develop breakthrough infections following vaccination have low levels of live-virus nAb. This article is highlighted in the In This Issue feature, p. 101.
<scp>ABO</scp> blood barrier to engraftment after allogeneic stem cell transplantation in sickle cell disease: A case‐story with two successive <scp>HLA</scp>‐matched sibling donors
Authors: Rabah Redjoul, Florence Beckerich, Gonzalo de Luna, Mathieu Leclerc, Nicolas Hebert, Ivan Sloma, Dehbia Menouche, Pablo Bartolucci, Sébastien Maury
Journal: American Journal of Hematology (2022)

All authors declare no conflict of interests. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
Changes in outcomes and factors associated with survival in melanoma patients with brain metastases
Authors: Merve Hasanov, Denái R Milton, Alicia Bea Davies, Elizabeth Sirmans, Chantal Saberian, Eliza L Posada, Sylvia Opusunju, Jeffrey E Gershenwald, Carlos A Torres-Cabala, Elizabeth M Burton, Rivka R Colen, Jason T Huse, Isabella C Glitza Oliva, Caroline Chung, Mary Frances McAleer, Susan L McGovern, Debra N Yeboa, Betty Y S Kim, Sujit S Prabhu, Ian E McCutcheon, Jeffrey S Weinberg, Frederick F Lang, Hussein A Tawbi, Jing Li, Lauren E Haydu, Michael A Davies, Sherise D Ferguson
Journal: Neuro-Oncology (2022)

Abstract Background Treatment options for patients with melanoma brain metastasis (MBM) have changed significantly in the last decade. Few studies have evaluated changes in outcomes and factors associated with survival in MBM patients over time. The aim of this study is to evaluate changes in clinical features and overall survival (OS) for MBM patients. Methods Patients diagnosed with MBMs from 1/1/2009 to 12/31/2013 (Prior Era; PE) and 1/1/2014 to 12/31/2018 (Current Era; CE) at The University of Texas MD Anderson Cancer Center were included in this retrospective analysis. The primary outcome measure was OS. Log-rank test assessed differences between groups; multivariable analyses were performed with Cox proportional hazards models and recursive partitioning analysis (RPA). Results A total of 791 MBM patients (PE, n = 332; CE, n = 459) were included in analysis. Median OS from MBM diagnosis was 10.3 months (95% CI, 8.9–12.4) and improved in the CE vs PE (14.4 vs 10.3 months, P &amp;lt; .001). Elevated serum lactate dehydrogenase (LDH) was the only factor associated with worse OS in both PE and CE patients. Factors associated with survival in CE MBM patients included patient age, primary tumor Breslow thickness, prior immunotherapy, leptomeningeal disease, symptomatic MBMs, and whole brain radiation therapy. Several factors associated with OS in the PE were not significant in the CE. RPA demonstrated that elevated serum LDH and prior immunotherapy treatment are the most important determinants of survival in CE MBM patients. Conclusions OS and factors associated with OS have changed for MBM patients. This information can inform contemporary patient management and clinical investigations.
Circular material flow in the intensive care unit—environmental effects and identification of hotspots
Authors: Nicole Hunfeld, Jan Carel Diehl, Maarten Timmermann, Pieter van Exter, Joris Bouwens, Savanna Browne-Wilkinson, Nine de Planque, Diederik Gommers
Journal: Intensive Care Medicine (2022)

The healthcare sector is responsible for 6-7% of CO2 emissions. The intensive care unit (ICU) contributes to these CO2 emissions and a shift from a linear system to a circular system is needed. The aim of our research was to perform a material flow analysis (MFA) in an academic ICU. Secondary aims were to obtain information and numbers on mass, carbon footprint, agricultural land occupation and water usage and to determine so-called "environmental hotspots" in the ICU.A material flow analysis was performed over the year 2019, followed by an environmental footprint analysis of materials and environmental hotspot identification.2839 patients were admitted to our ICU in 2019. The average length of stay was 4.6 days. Our MFA showed a material mass inflow of 247,000 kg in 2019 for intensive care, of which 50,000 kg is incinerated as (hazardous) hospital waste. The environmental impact per patient resulted in 17 kg of mass, 12 kg CO2 eq, 300 L of water usage and 4 m2 of agricultural land occupation per day. Five hotspots were identified: non-sterile gloves, isolation gowns, bed liners, surgical masks and syringes (including packaging).This is the first material flow analysis that identified environmental risks and its magnitude in the intensive care unit.
Chlorogenic Acid‐Conjugated Nanoparticles Suppression of Platelet Activation and Disruption to Tumor Vascular Barriers for Enhancing Drug Penetration in Tumor
Authors: Yue Ke, Zhifang Ma, Hongbo Ye, Xinghua Guan, Zehong Xiang, Yu Xia, Qiang Shi
Journal: Advanced Healthcare Materials (2022)

Abstract Hypercoagulation threatens the lives of cancer patients and cancer progression. Platelet overactivation attributes to the tumor‐associated hypercoagulation and maintenance of the tumor endothelial integrity, leading to limited intratumoral perfusion of nanoagents into solid tumors in spite of the enhanced penetration and retention effect (EPR). Therefore, the clinical application of nanotherapeutics in solid cancer still faces great challenges. Herein, this work establishes platelet inhibiting nanoagents based on Fe III ‐doped C 3 N 4 coloaded with the chemotherapy drug and the antiplatelet drug chlorogenic acid (CA), further opening tumor vascular endothelial junctions, thereby disrupting the tumor vascular endothelial integrity, and enhancing drug perfusion. Moreover, CA not only damages the cancer cells but also potentiates the cytotoxicity induced by the chemotherapy drug doxorubicin, synergistically ablating the tumor tissue. Further, the introduction of CA relieves the original causes of the hypercoagulable state such as tissue factor (TF), thrombin, and matrix metalloproteinases (MMPs) secreted by cancer cells. It is anticipated that the hypercoagulation‐ and platelet‐inhibition strategy by integration of phenolic acid CA into chemotherapy provides insights into platelet inhibition‐assisted theranostics based on nanomedicines.
Graphene‐Based Nanocomposites as Antibacterial, Antiviral and Antifungal Agents
Authors: Seda Gungordu Er, Mohan Edirisinghe, Tanveer A. Tabish
Journal: Advanced Healthcare Materials (2022)

Over the past decade, there have been many interesting studies in the scientific literature about the interaction of graphene-based polymeric nanocomposites with microorganisms to tackle antimicrobial resistance. These studies have reported variable intensities of biocompatibility and selectivity for the nanocomposites toward a specific strain, but it is widely believed that graphene nanocomposites have antibacterial, antiviral, and antifungal activities. Such antibacterial activity is due to several mechanisms by which graphene nanocomposites can act on cells including stimulating oxidative stress; disrupting membranes due to sharp edges; greatly changing core structure mechanical strength and coarseness. However, the underlying mechanisms of graphene nanocomposites as antiviral and antifungal agents remain relatively scarce. In this review, recent advances in the synthesis, functional tailoring, and antibacterial, antiviral, and antifungal applications of graphene nanocomposites are summarized. The synthesis of graphene materials and graphene-based polymeric nanocomposites with techniques such as pressurized gyration, electrospinning, chemical vapor deposition, and layer-by-layer self-assembly is first introduced. Then, the antimicrobial mechanisms of graphene membranes are presented and demonstrated typical in vitro and in vivo studies on the use of graphene nanocomposites for antibacterial, antiviral, and antifungal applications. Finally, the review describes the biosafety, current limitations, and potential of antimicrobial graphene-based nanocomposites.
An RNA-targeting CRISPR–Cas13d system alleviates disease-related phenotypes in Huntington’s disease models
Authors: Kathryn H. Morelli, Qian Wu, Maya L. Gosztyla, Hongshuai Liu, Minmin Yao, Chuangchuang Zhang, Jiaxu Chen, Ryan J. Marina, Kari Lee, Krysten L. Jones, Megan Y. Huang, Allison Li, Charlene Smith-Geater, Leslie M. Thompson, Wenzhen Duan, Gene W. Yeo
Journal: Nature Neuroscience (2022)

Abstract Huntington’s disease (HD) is a fatal, dominantly inherited neurodegenerative disorder caused by CAG trinucleotide expansion in exon 1 of the huntingtin ( HTT ) gene. Since the reduction of pathogenic mutant HTT messenger RNA is therapeutic, we developed a mutant allele-sensitive CAG EX RNA-targeting CRISPR–Cas13d system (Cas13d–CAG EX ) that eliminates toxic CAG EX RNA in fibroblasts derived from patients with HD and induced pluripotent stem cell-derived neurons. We show that intrastriatal delivery of Cas13d–CAG EX via an adeno-associated viral vector selectively reduces mutant HTT mRNA and protein levels in the striatum of heterozygous zQ175 mice, a model of HD. This also led to improved motor coordination, attenuated striatal atrophy and reduction of mutant HTT protein aggregates. These phenotypic improvements lasted for at least eight months without adverse effects and with minimal off-target transcriptomic effects. Taken together, we demonstrate proof of principle of an RNA-targeting CRISPR–Cas13d system as a therapeutic approach for HD, a strategy with implications for the treatment of other dominantly inherited disorders.